The project we are working on is design and synthesis of nonsteroid compounds as potential agonists or antagonists of steroid hormone receptors. The steroid hormone receptors represent a very important family of drug targets. Several ligands of this class of receptors such as estrogen and tamoxifen have already gained extensive clinical applications. However, ligands of a steroid structure face the following drawbacks. First, they do not possess enough selectivity; one ligand can often activate or suppress more than one receptor, which leads to serious side effects. Secondly, it is synthetically difficult to introduce diverse functional groups onto the steroid backbone, which harnesses the discovery of more selective derivatives of the known compounds. Tamoxifen is a potent estrogen receptor antagonist which does not have a steroid nucleus. Recently, the crystal structure of this compound complexed with the binding domain of estrogen receptor has been published, which provides new information about the binding mode and the structure-activity relationship of nonsteroid ligands. This project intends to exploit the above information and develop a series of nonsteroid compounds with diverse functional groups on a trans-1,2-diarylethene backbone in an effort to search for more selective ligands and to study the structure-activity/selectivity relationships of nonsteroid ligands. For these purposes, we are using DOCK, MIDAS, and SYBYL as major software and SGI workstations as hardware support, all of which are available in the UCSF Computer Graphics Lab.